Familial hypertrophic cardiomyopathy is an inherited autosomal dominant disorder of heart muscle characterized by unexplained ventricular hypertrophy with myofibrilar disarray. We have recently mapped the gene bearing defects responsible for this disorder in two unrelated families (families A and B) to chromosome 14 band q11. Further, we have very suggestive evidence that affected members of family B bear defects in a cardiac myosin heavy chain gene (located on chromosome 14 band q11). Here we propose to confirm that the gene defect responsible for FHC in affected members of the unrelated family A, is also in a myosin heavy chain gene (Alpha or Beta). Further we will determine whether expression of defective human cardiac myosin genes in rat cytes causes myofibrillar disarray and whether expression of this gene in a transgenic mouse causes cardiac hypertrophy. Finally we will attempt to define the features of myosin that can count for this disorder. Specifically we propose to: 1. Define the structure of the cardiac myosin heavy chain genes in affected members of A and other families whose FHC locus is genetically linked to chromosome 14. 2. Determine whether the altered nucleotide sequences found in the mutant myosin genes cause hypertrophic cardiomyopathy. 3. Construct variants of the cardiac myosin heavy chain genes and define those regions that can cause cardiac hypertrophy. 4. Demonstrate that a defective myosin molecule is present in cardiac tissue of affected individuals.